Background: BRCA1/2are crucial genes in the homologous recombination repair (HRR) pathway, and loss-of-function mutations in these genes are associated with response to PARP-inhibitors (PARPi). However, it remains unclear to which extent patients with alterations in other HRR-pathway associated genes may benefit from PARPi. In the Drug Rediscovery Protocol (DRUP, NCT02925234), patients receive off-label drugs based on their tumor molecular profile. Here, we present the results from two separate DRUP-cohorts to evaluate the efficacy and safety of olaparib in patients with tumors harboring mutations in ATM, CKD12, PPP2R2A, CHEK1/2 or RAD51B. Methods: Adult patients with progressive, treatment-refractory tumors with loss-of-function mutations in ATM (cohort A) or other HRR-pathway associated genes as described above (cohort B), and measurable disease according to RECISTv1.1 were eligible for inclusion. Patients received olaparib (300mg) twice daily, until disease progression (assessments every 8 weeks) or unmanageable toxicity. The primary endpoints of DRUP are clinical benefit (CB: defined as confirmed objective response (OR) or stable disease (SD) ≥16 weeks) and safety. Per protocol, patients were enrolled using a Simon-like two-stage model. Whole genome sequencing (WGS) was performed on pre-treatment biopsies to identify potential biomarkers for CB. Results: A total of 25 evaluable patients with 10 different tumor types (n = 10 prostate cancer; n = 5 colorectal cancer; n = 2 non-small cell lung cancer; n = 2 adenoid cystic carcinoma; n = 6 other) were enrolled in cohort A. CB was observed in 8/25 patients (32%; 95% CI 14.9%-53%); one patient achieved an OR (4%). Median progression-free (PFS) and overall survival (OS) were 3.4 months (95% CI 1.8-5.3) and 9.2 months (95% CI 5.2-21.3), respectively. In cohort B, 24 evaluable patients with 4 different tumor types (n = 18 prostate cancer; n = 3 ovarian cancer; n = 2 pancreatic; n = 1 breast cancer) were included. These patients harbored loss-of-function mutations in CDK12 (n = 9), PPP2R2A (n = 6), CHEK1/2 (n = 5), and RAD51B (n = 4). CB was observed in 10/24 patients (41.7%; 95% CI 22.1%-63.4%), with loss-of-function mutations in CDK12 (n = 7), RAD51B (n = 2) and CHEK2 (n = 1). Median PFS and OS were 3.5 months (95% CI 3.4-6.6) and 8.1 months (95% CI 6.6-14.2), respectively. Overall, no unexpected toxicities were observed. Biomarker analysis (HR-deficiency core, loss of heterozygosity, telomeric allelic imbalance and large-scale transitions) is currently ongoing. Conclusions: Olaparib has clinical benefit in patients with progressive, treatment-refractory tumors harboring mutations in ATM, CDK12, CHEK2 or RAD51B. The ongoing biomarker analysis aims to identify potential biomarkers that can help refining patient selection and thereby improving clinical benefit rate. Clinical trial information: NCT02925234.